MDA 2025: Apitegromab could fill unmet SMA needs, executive says
Scholar Rock's CMO sees 'meaningful difference' in muscle-targeted therapy
The muscle-strengthening therapy apitegromab is being considered for approval by the U.S. Food and Drug Administration (FDA) as an add-on treatment for spinal muscular atrophy (SMA), with a decision expected around the start of fall.
Scholar Rock, the company developing apitegromab, applied seeking FDA approval earlier this year. This week, the FDA granted priority review to the application and set Sept. 22 as its decision date, the company announced. A similar approval application is under review in the European Union.
“We are delighted with the priority review designation … which is consistent with the potential of apitegromab to be a transformative therapy and the first muscle-targeted treatment” for SMA, Jay Backstrom, MD, Scholar Rock’s CEO and president, said in the release.
Apitegromab acts like a brake on protein that restricts muscle growth
According to the company’s chief medical officer, Jing Marantz, MD, PhD, Scholar Rock is gearing up for a potential U.S. commercial launch.
If the FDA approves apitegromab, the therapy could be available before this year’s end, Marantz told SMA News Today during an interview at the recent annual Muscular Dystrophy Association (MDA) conference. The company anticipates a European launch for 2026.
Jing L. Marantz, MD, PhD, is Scholar Rock’s chief medical officer. (Photo by Kellie Benn)
Chiefly, SMA is caused by mutations that lead to abnormally low levels of the SMN protein. Several disease-modifying treatments, which work to boost levels of this protein and help to slow disease progression, are approved, but SMA symptoms like muscle weakness can continue to affect patients.
Apitegromab has the potential to fill unmet patient needs by providing an option that, when given in addition to SMN-targeting therapies, can boost muscle strength and “actually make a meaningful difference on people’s lives,” Marantz said.
Specifically, apitegromab is designed to boost muscle strength by blocking the activity of a protein called myostatin. Marantz likens myostatin to a brake that naturally slows muscle growth, preventing excessive growth.
“When you take the brake off, muscle fiber grows bigger and stronger. So therefore when you inhibit [myostatin], it’s kind of like taking off the brake,” Marantz said.
Many previous attempts to increase muscle strength by targeting myostatin failed in clinical testing, she noted, in large part due to safety issues. This is partly because the active version of myostatin has a similar molecular structure to several signaling molecules important for regulating a variety of bodily functions; drugs designed to block active myostatin can inadvertently interfere with them. Apitegromab gets around this problem, Marantz explained, by targeting a precursor form of myostatin that has a different molecular structure, making it easier to avoid off-target effects while still blocking the protein’s activity.
Benefits seen in Phase 3 trial in children, young adults with SMA types 2 and 3
The application for apitegromab’s approval is supported mainly by data from the Phase 3 SAPPHIRE (NCT05156320) trial. It enrolled children and young adults, ages 2 to 21, with SMA type 2 or type 3 who were able to sit independently and were taking the SMN-targeting therapies Spinraza (nusinersen) or Evrysdi (risdiplam). Patients were randomly assigned to apitegromab or a placebo for about a year. In those ages 2 to 12, two different doses (10 and 20 mg/kg) were tested, but both yielded similar results.
How treatment affected scores on the Hammersmith Functional Motor Scale Expanded (HFMSE), a standardized measure of motor function, was the study’s main goal. Results showed that HFMSE scores improved slightly in patients given apitegromab, and worsened for those on the placebo. By the trial’s end, there was an average 1.8-point difference favoring apitegromab over a placebo.
According to Marantz, this magnitude of difference means that, on average, patients given apitegromab either were more likely to do one or two new things or to not lose any functional abilities, relative to patients on the placebo.
Treated patients reported being able to do things they couldn’t do before
Scholar Rock’s application also includes data from the open-label Phase 2 TOPAZ clinical trial (NCT03921528), which similarly indicated apitegromab helped to boost motor function in combination with SMN-targeting therapies. As part of this trial, a survey asked participants about how the therapy affected them. According to Marantz, the types of improvements reported in TOPAZ were similar to those seen with apitegromab-treated patients in SAPPHIRE.
“They are able to do things that they [couldn’t] do before,” she said. “Like they can now use markers to draw. They can crawl from one side of the room to the other side of the room. They can brush their teeth. They can now open a container.” All these changes, she added, mean that patients “are now gaining more freedom to access the world around them.”
Marantz emphasized that HFMSE scores in SAPPHIRE favored apitegromab over the placebo across all pre-specified patient groups, including those defined by age or choice of disease-modifying therapy.
“When we look at the top-line [result], it’s positive. We then look at the next layer, all the subgroups that [are] pre-specified, they also all favor apitegromab. That’s really good,” she said.
Secondary SAPPHIRE motor function goals also tended to favor apitegromab over the placebo, though differences here mostly were not statistically significant, meaning they could be due to chance. Still, Marantz considered it encouraging that all motor function measures tended to show better outcomes with apitegromab.
“The most important point is that every one of those three key secondary [trial goals] favors apitegromab. … That is a testament to the robustness of the data,” Marantz said. “No matter how you push it, the data stands firm.”
SAPPHIRE specifically tested apitegromab in children and young adults with SMA types 2 or 3. But Marantz said there’s “no reason to believe that the data that we have … is not [applicable] to the broader [patient] population,” given that all types of SMA share the same underlying disease biology.
Possibility of more convenient ways of administering add-on treatment
In trials, apitegromab was administered via infusion into the bloodstream once every four weeks. According to Marantz, a first and possibly a second infusion is usually given slowly, over the course of about two hours. Assuming no adverse reactions, subsequent infusions can usually be given in about one hour, with a 15-minute monitoring period after the infusion ends so any worrisome reactions can be quickly addressed.
Marantz noted that, assuming apitegromab gets approved, Scholar Rock is working toward systems that would allow patients to infuse apitegromab at the home rather than needing to go to a hospital or infusion center. “That will give a lot of freedom,” she said.
Scholar Rock also has launched preclinical studies into a subcutaneous (under-the-skin) injection version of apitegromab that could offer more convenience. Tests in animal models so far have been encouraging, Marantz said.
In SAPPHIRE, apitegromab was quite well tolerated overall, with the most common safety issues being infection, digestive upset, fever, and headache, and the like — all things common among children with or without SMA, Marantz noted.
Somewhat higher rates of pneumonia were reported among patients given apitegromab than the placebo. Most likely, Marantz said, this is because pneumonia rates were uncommonly low across the placebo group. The COVID-19 pandemic may also have influenced these safety findings, she added.
“We don’t have any major concerns with respect to side effect profile. That’s the overall takeaway,” Marantz said.
Scholar Rock recently announced plans for a new clinical trial, called OPAL, of apitegromab in babies and toddlers with SMA younger than age 2, the minimum age for SAPPHIRE. This study, Marantz said, will assess apitegromab’s safety and efficacy in very young patients, as well as making sure the right dose is used.
Note: The SMA News Today team is providing live coverage of the 2025 MDA Clinical & Scientific Conference in Dallas. Go here to see the latest stories from the conference.
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